A method of preparing poly-substituted acylbenzenes

Description

[0001] This invention relates to a method of preparing poly-substituted acylbenzenes and more particularly to synthesizing these acylbenzenes by means of a perfluoro sulfonic acid polymer acylating catalyst.

[0002] When an acyl halide or equivalent is reacted with 2-bromo-1,3-dimethoxybenzene to form the corresponding acylbenzene it has been found that rearrangement products either predominate or at least are present as major contaminants when usual acylating or Friedel-Crafts catalysts are employed. Such rearrangement products involve bromine migration from the 2 to 4 position, e.g.,

[0003] As reported by G. A. Olah, et al, in Synthesis, 1978, 672, a solid perfluorinated resin sulfonic acid, commercially available from E. I. DuPont de Nemours as ^(R)Nafion H, can be employed as an acylating catalyst in reactions between acyl halides, anhydrides, or mixtures of acids and their anhydrides and other substituted benzenes. However, it has not heretofore been reported or suggested that such a perfluorinated resin sulfonic acid could function to prevent the formation of rearrangement products when 2-bromo-1,3-dimethoxybenzene is employed.

[0004] Therefore, the present invention is directed to a method of preparing poly-substituted acylbenzenes of the formula I

and more particularly to synthesizing the acylbenzenes by means of a perfluorosulfonic acid polymer acylating catalyst.

[0005] The method comprises reacting

a) a compound of the formula

b) a mixture of the compounds of the formula

c) a compound of the formula

wherein R is C₁―C₆-alkyl or a mono- or polycyclic aromatic or a heteroaromatic radical which may be substituted with the radicals X_m and Y where X and Y are the same or different and represent halogen, C₁―C₆-alkyl, C₁―C₆-alkoxy, C₁―C₆-alkylthio, trifluoromethyl or nitro, and m and n are the same or different integers of 1 or 2, with a compound of the formula II

wherein R, and R₂ are the same or different and represent C₁―C₆-alkoxy or hydroxy, in the presence of an acylating agent comprising a perfluorosulfonic acid polymer.

[0006] The present invention is described primarily in terms of acylating bromo-1,3-dimethoxybenzene to form a substituted benzophenone without essentially forming a contaminating rearrangement acylating product; however, it will be understood that such description is exemplary only and is for purposes of exposition and not for purposes of limitation. It will be readily appreciated that the inventive concept described is equally applicable to acylating 2-bromo-1,3-dimethoxybenzene or 2-bromo-1,3-dihydroxybenzene with an acylhalide or equivalent such as an acylanhydride or mixture of such an anhydride and its corresponding acid.

[0007] In the case where the desired product is a benzopherone, a benzoyl halide of the formula

is preferred. Alternatively if a different acylbenzene is desired an opposite first reactant of one of the above formulae is selected wherein R is C₁―C₆-alkyl, or another appropriately substituted aromatic group or a heteroaromatic group, including but not limited to one of the following: naphthylyl; e.g.

furyl (a or A), e.g.

etc.

[0008] A second reactant of the formula II

where R, and R₂ are the same or different and represent C,-alkoxy or hydroxy, e.g., 2-bromo-1,3-methoxybenzene, is selected.

[0009] A suitable catalyst for the method according to the present invention comprises a perfluorosulfonic acid polymer. Such a polymer comprises a polymeric material obtained from a fluorocarbon vinyl ether having the formula III

where R_f represents fluorine or a perfluoroalkyl radical having from 1 to 10 carbon atoms, Y represents fluorine or the trifluoromethyl radical, n is an integer of 1 to 3 inclusive, and M represents fluorine, the hydroxyl radical, the amino radical or a radical having the formula -OMe where Me is an alkali metal or a quaternary ammonium radical. The vinyl ether of the formula III is readily homopolymerized or copolymerized to form the catalysts of the present invention. Preferred comonomers for copolymerization include ethylene or halogenated ethylenes. It is to be understood, however, the copolymerization of the vinyl ether are achieved with any ethylenically unsaturated comonomer capable of homopolymerization. Additional fluorinated monomers may also be copolymerized with ethylene or the halogenated ethylenes and the vinyl ethers, such third monomer being for example a perfluoro alpha-olefin, e.g. hexafluoropropylene, or a perfluoro (alkyl vinyl ether) of the type

where n' is 0 to 5, inclusive.

[0010] A preferred catalyst is the group of solid perfluoro sulfonic acid resins or polymers commercially obtained from E. I. DuPont de Nemours and designated as ^(R)Nafion persulfonic acid products. These ^(R)Nafion products are copolymers of the above-described vinyl ether and tetrafluoroethylene and are supplied in the salt form, e.g., potassium sulfonate. The salt form is readily converted to the acid form by treatment with a mineral acid, e.g. nitric acid, washing with water and drying at 105°C-1 10°C for about twelve hours. The ^(R)Nafion persulfonic acids have an empirical formule of

where Z is the number of repeated units, and typically have an equivalent weight within the range of 1100 and 1800.

[0011] The above perfluorosulfonic acid resins or polymers and their preparation are fully described in Connally et al., U.S. Patent No. 3,282,875.

[0012] The first reactant, the second reactant and the perfluorosulfonic acid polymer catalyst are combined and reacted under the usual Friedel-Crafts reaction conditions. Typically the reactants and catalyst are heated to reflux for a sufficient period of time to achieve the desired acylation, e.g. 22-24 hours.

[0013] Surprisingly and unexpectedly, the use of the perfluorosulfonic acid polymer catalyst yields the desired product, 4-acyl-2-bromo-1,3-dialkoxy- or dihydroxy-benzene, which is free from contamination or formation of significant rearrangement products. This is a surprising and unexpected result since with the usual Friedel-Crafts acylation catalysts, e.g., Lewis acids such as SnCl₄, ZnCl₂, AICI₃, etc., such rearrangement products are obtained and may often predominate. Such rearrangement products, it is believed, occur because the usual Friedel-Crafts catalysts promote metathesis of the starting material such as 2-bromo-1,3-dimethoxybenzene to yield 4,6-dibromo-1,3-dimethoxybenzene, 2,4-dimethoxy- bromobenzene and 1,3-dimethoxybenzene. It is this "rearranged starting material" which reacts with the requisite acylating agents to give poor yields of the desired acyl-2-bromo-1 ,3-dimethoxybenzenes. Surprisingly and unexpectedly the catalysts of the instant process do not cause such rearrangements but promote instead only the desired acylation.

Example I

[0014] 2-Bromo-1,3-dimethoxybenzene [32.60 g; 0.150 mole] and 2-fluorobenzoyl chloride [30.0 g; 0.189 mole] are dissolved in 150 ml of 1,2-dichloro ethane. To this mixture is added ten grams of (^RINafion H, commercially obtained from E. I. DuPont de Nemours. The reaction mixture is brought to reflux and is stirred. After refluxing for 22 hours the catalyst is filtered off and washed with dichloroethane. The combined organic phase is concentrated under reduced pressure to give crystalline material after trituration with hexane. Recrystallization from isopropanol gives 38.5 grams [70% yield] of 3-bromo-2,4-dimethoxy-2'-fluorobenzophenone, m.p. 88-91°C, as the sole benzophenone product.

[0015] After an additional recrystallization from isopropanol, the melting point is raised to 92-93°C.

Example II

[0016] For comparison purposes, the procedure of Example I is repeated except that the following Friedel-Crafts acylating agents are employed

In all cases, either a desired reaction product is not obtained or a mixture of 3-bromo-2,4-dimethoxy-2'-fluorobenzophenone [desired product], 5-bromo-2,4-dimethoxy-2'-fluorobenzophenone [undesired rearrangement product] and/or the various rearranged starting material as heretofore described is obtained.

[0017] The following are comparative procedures for the various catalysts employed which graphically illustrate the surprising and unexpected superiority of the perfluorosulfonic acid polymer catalysts:

[a] SnCl₄

[0018] 2-Fluorobenzoyl chloride (1.58 g; 0.010 mole) is dissolved in 15 ml of 1,2-dichloroethane at ice bath temperature. Stannic chloride (2.58 g; 0.010 mole) is added and the reaction is stirred 5 minutes, after which 2-bromo-1,3-dimethoxybenzene is added (2.17 g; 0.010 mole) in 3 ml of 1,2-dichloroethane. After 2 hours, the following mixture of products is obtained, as analyzed by the technique of mass spectrometry/gas chromatography: 2-bromo-1,3-dimethoxybenzene (9.5%), 4-bromo-1,3-dimethoxybenzene (trace,), 4,6-dibromo-1,3-dimethoxybenzene (8.0%), 2'-fluoro-2,4-dimethoxybenzophenone (11.1%), 3-bromo-2'-fluoro-2,4-dimethoxybenzophenone (22.9%), 5-bromo-2'-fluoro-2,4-dimethoxybenzophenone (13.7%).

[b] ZnCl₂

[0019] 2-Bromo-1,3-dimethoxybenzene (2.17 g; 0.010 mole) is dissolved in 7 ml of dichloromethane and freshly fused zinc chloride (1.36 g; 0.010 mole) is added. After stirring 15 minutes at room temperature, 2-fluorobenzoyl chloride (1.58 g; 0.010 mole) is added. After stirring 3 days at room temperature, the following mixture is obtained, as analyzed by gas chromatography: 2-bromo-1,3-dimethoxybenzene (9%),,4-bromo-1,3-dimethoxybenzene (trace), 4,6-dibromo-1,3-dimethoxybenzene (7%), 2'-fluoro-2,4-dimethoxybenzophenone (22%), 3-bromo-2'-fluoro-2,4-dimethoxybenzophenone (4%), 5-bromo-2'-fluoro-2,4-dimethoxybenzophenone (31%).

[c] AlCl₃

[0020] 2-Bromo-1,3-dimethoxybenzene (217 g; 1.0 mole) and 2-fluorobenzoyl chloride (158 g; 1.0 mole) are dissolved in 1,2-dichloroethane and aluminum chloride (1.33 g; 1.0 mole) is added slowly. The reaction mixture is refluxed for 2 hours and then worked up with 5% hydrochloric acid. In this way a 1:2 mixture of 5-bromo-2'-fluoro-2-hydroxy-4-methoxybenzophenone and 3-bromo-2'-fluoro-2-hydroxy-4-methoxybenzophenone is obtained, as indicated by nuclear magnetic resonance (NMR). A quantity of this mixture is separated by preparative high pressure liquid chromatography into its two components, 5-bromo-2'-fluoro-2-hydroxy-4-methoxybenzophenone, m.p. 127-129°C and 3-bromo-2'-fluoro-2-hydroxy-4-methoxybenzophenone, m.p. 137-139°C.

[d] BBr₂

[0021] 2-Bromo-1,3-dimethoxybenzene (4.34 g; 0.020 mole) is dissolved in 15 ml of dichloromethane and 2-fluorobenzoyl chloride (3.16 g; 0.020 mole) is added. This mixture is chilled in an ice bath as boron tribromide is added (3.10 g; 0.020 mole). The reaction is brought to reflux and refluxed 16 hours. Thin layer chromatography shows qualitatively an equal mixture of 5-bromo-2'-fluoro-2-hydroxy-4-methoxybenzophenone and 3-bromo-2'-fluoro-2-hydroxy-4-methoxybenzophenone.

[e] TiCl₄

[0022] 2-Bromo-1,3-dimethoxybenzene (2.17 g; 0.010 mole) and 2-fluorobenzoyl chloride (1.58 g; 0.010 mole) are dissolved in 15 ml of 1,2-dichloroethane at -5°C and titanium tetrachloride (1.89 g; 0.010 mole) is added. After 2.5 hours gas chromatography shows that 2-bromo-1,3-dimethoxybenzene is entirely consumed and the following mixture of products is present: 4,6-dibromo-1,3-dimethoxybenzene (4%), 2'-fluoro-2,4-dimethoxybenzophenone (10%), 3-bromo-2'-fluoro-2,4-dimethoxybenzophenone (46%), 5-bromo-2'-fluoro-2,4-dimethoxybenzophenone (34%).

Example III

[0023] As an illustration of the effect that usual Friedel-Crafts catalysts have on the starting 2-bromo-1,3-dimethoxybenzene, 2.17 g (0.010 mole) of this material is dissolved in 15 ml of 1,2-dichloroethane and ferric chloride (1.62 g; 0.010 mole) is added. After 30 minutes at room temperature gas chromatography shows that 2-bromo-1,3-dimethoxybenzene is almost completely consumed and a mixture of 4-bromo-1,3-dimethoxybenzene, 1,3-dimethoxybenzene, and 4,6-dibromo-1,3-dimethoxybenzene is in its place.

[0024] A similar experiment using the perfluorosulfonic acid polymer catalysts of the instant process in place of the ferric chloride affords only unchanged 2-bromo-1,3-dimethoxybenzene.

Claims

₁. A method of preparing a poly-substituted acylbenzene having a structural formula I

where R_i and R₂ are the same or different and represent C₁―C₆-alkoxy or hydroxy, R represents (a) C₁―C₆-alkyl, or (b) a mono- or polycyclic aromatic or heteroaromatic radical, which radicals may be substituted with X_m or Y_n where X and Y are the same or different and represent halogen, C₁―C₆-alkyl, C₁―C₆-alkoxy, C₁―C₆-alkylthio, trifluoromethyl or nitro, and m and n are the same or different integers of 1 or 2, which comprises reacting

a) a compound of the formula

b) a mixture of the compounds

c) a compound of the formula

where R is as defined above, with a second reactant having the formula II

where R_i and R₂ are as defined above, in the presence of an acylating agent comprising a perfluorosulfonic acid polymer.

2. The method as defined in claim 1 wherein said perfluoro sulfonic acid polymer is

(1) a homopolymer of a vinyl ether having the formula

where R_f represents fluorine or a perfluoroalkyl radical having from 1 to 10 carbon atoms, Y represents fluorine or the trifluoromethyl radical, n is an integer of 1 to 3 inclusive, and M represents fluorine, the hydroxyl radical, the amine radical or a radical having the formula -OMe where Me is an alkali metal or a quaternary ammonium radical or

(2) a copolymer of the vinyl ether of (1) above and a monomer which may be (a) ethylene, (b) a halogenated ethylene or (c) at least one of monomer selected from ethylene and halogenated ethylenes and at least one monomer selected from perfluorinated alpha-olefins and perfluoro alkyl vinyl ethers having the formula

where n' is 0 to 5.

3. The method as defined in claim 2 wherein R represents phenyl, naphthyl, α-thienyl, β-thienyl, α-furyl, β-furyl, α-pyridyl, β-pyridyl or γ-pyridyl, which may be substituted with X_m or Y_n where X, Y, m and n are as defined.

4. The method as defined in claim 3, wherein R is

and X, Y, m and n are as defined.

5. The method as defined in claim 2, wherein said vinyl ether is copolymerized with at least a halogenated ethylene.

6. The method as defined in claim 5, wherein said vinyl ether is copolymerized with tetrafluoroethylene.

7. The method as defined in claim 6, wherein said copolymer has a structural formula

where Z represents a number of repeating units.

8. The method as defined in claim 7, wherein said copolymer has an equivalent weight within the range of 1100 to 1800.

9. The method as defined in claim 1, wherein said catalyst is a copolymer of a vinyl ether having the formula

where M represents fluorine, the hydroxyl radical, the amino radical or a radical having the formula -OMe where Me represents an alkali metal or a quaternary ammonium radical, and tetrafluoroethylene.

10. The method as defined in claim 1, wherein said catalyst is a copolymer of a vinyl ether having a formula

and tetrafluoroethylene.

11. The method as defined in claim 1, wherein said catalyst is a copolymer of a vinyl ether having a formula

where Me is an alkali metal or a quaternary ammonium radical and tetrafluoroethylene.

Revendications

1. Procédé de préparation d'un acylbenzène poly-substitué répondant à la formule développée:

dans laquelle R₁ et R₂ sont identiques ou différents et représentent un groupe alcoxy en C₁―C₆ ou hydroxy, R représente (a) un groupe alcoyle en C₁―C₆ ou (b) un radical aromatique ou hétéroaromatique mono- ou polycyclique, lesquels radicaux peuvent être substitués par X_m ou Y_n, où X et Y sont identiques ou différents et représentent un halogéne, un groupe alcoyle en C₁―C₆, alcoxy en C₁―C₆, alcoylthio en C₁―C₆, trifluorométhyle ou nitro, et m et n sont les nombres entiers identiques ou différents 1 ou 2, caractérisé en ce qu'on fait réagir:

a) un composé de formule

ou

b) un mélange des composés

c) un composé de formule

dans laquelle R est tel que défini ci-dessus, avec un second réactif répondant à la formule Il

dans laquelle R₁ et R₂ sont tels que définis ci-dessus, en présence d'un agent d'acylation comprenant un polymère d'acide perfluorosulfonique.

2. Procédé selon la revendication 1, caractérisé en ce que le polymère d'acide perfluorosulfonique est:

(1) un homopolymère d'un éther vinylique de formule

dans laquelle R_f représente le fluor ou un radical perfluoroalcoyle ayant de 1 à 10 atomes de carbone, Y représente le fluor ou le radical trifluorométhyle, n est un nombre entier de 1 à 3 inclusivement, et M représente le fluor, le radical hydroxyle, le radical amine ou un radical de formule -OMe où Me est un métal alcalin ou un radical ammonium quaternaire, ou

(2) un copolymère de l'éther vinylique de (1) ci-dessus et d'un monomère qui peut être (a) l'éthylène, (b) un éthylène halogéné ou (c) au moins un monomère choisi parmi l'éthylène ou des éthylènes halogénés et au moins un monomère choisi parmi des alpha-oléfines perfluorées et des éthers perfluoro-alcoyl vinyliques de formule:

où n' est compris entre 0 et 5.

3. Procédé selon la revendication 2, caractérisé en ce que R représente un groupe phényle, naphtyle, α-thiényle, β-thiényle, α-furyle, β-furyle, α-pyridyle, β-pyridyle ou γ-pyridyle, qui peut être substitué avec X_m ou Y_n, X, Y, m et n étant tels que définis.

4. Procédé selon la revendication 3, caractérisé en ce que R est

et X, Y m et n sont tels que définis.

5. Procédé selon la revendication 2, caractérisé en ce que l'éther vinylique est copolymérisé avec au moins un éthylène halogéné.

6. Procédé selon la revendication 5, caractérisé en ce que l'éther vinylique est copolymérisé avec du tétetrafluoroéthylène.

7. Procédé selon la revendication 6, caractérisé en ce que le copolymère répond à la formule

dans laquelle Z représente le nombre de motifs récurrents.

8. Procédé selon la revendication 7, caractérisé en ce que le copolymère a une masse équivalente de l'ordre de 1100 à 1800.

9. Procédé selon la revendication 1, caractérisé en ce que le catalyseur est un copolymère d'un éther vinylique de formule

dans laquelle M représente le fluor, le radical hydroxyle, le radical amino ou un radical de formule -OMe où Me représente un alcalin ou un radical ammonium quaternaire, et de tétrafluoroéthylène.

10. Procédé selon la revendication 1, caractérisé en ce que le catalyseur est un copolymère d'un éther vinylique de formule

et de tétrafluoroéthylène.

11. Procédé selon la revendication 1, caractérisé en ce que le catalyseur est un copolymère d'un éther vinylique de formule

dans laquelle Me est un métal alcalin ou un radical ammonium quaternaire, et de tétrafluoroéthylène.

Ansprüche

1. Verfahren zur Herstellung eines polysubstituierten Acylbenzols der Formel I

worin R₁ und R₂ gleich oder verschieden sind und für C₁―C₆-Alkoxy oder Hydroxy stehen, R a) eine C₁―C₆-Alkylgruppe oder b) eine mono- oder polyzyklische aromatische oder heteroatomische Gruppe bedeutet, die durch X_m oder Y_n substituiert sein kann, wobei X und Y gleich oder verschieden sein können und ein Halogenatom, C₁―C₆-Alkyl, C₁―C₆-Alkoxy, C₁―C₆-Alkylthio, Trifluormethyl oder Nitro bedeuten und m und n gleich oder verschieden sein können und 1 oder 2 bedeuten, dadurch gekennzeichnet, daß man

a) eine Verbindung der Formel

b) ein Gemisch aus Verbindungen der Formeln

c) eine Verbindung der Formel

worin R obige Bedeutung hat,
mit einer Verbindung der Formel II

worin R₁ und R₂ die obigen Bedeutungen haben, in Gegenwart eines ein Perfluorsulfonsäurepolymeres enthaltenden Acyliermittels umsetzt.

2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man als Perfluorsulfonsäurepolymer

1) ein Vinylätherhomopolymer der Formel

worin R_f ein Fluoratom oder eine Perfluoralkylgruppe mit 1 bis 10 Kohlenstoffatomen darstellt, Y ein Flouratom oder eine Trifluormethylgruppe, n eine ganze Zahl von 1 bis 3 und M ein Fluoratom, Hydroxy, Amino oder eine Gruppe der Formel -OMe, worin Me für ein Alkalimetall oder eine quaternäre Ammoniumgruppe steht, bedeuten oder

2) ein Copolymer aus einem Vinyläther der obigen Formel (1) und a) Ethylen oder b) halogeniertem Ethylen oder c) wenigstens einem Ethylen- oder halogeniertem Ethylenmonomeren und wenigstens einem perfluorierten α-Olefinmonomeren oder perfluorierten Alkylvinyläthermonomeren der Formel

worin n' 0 oder eine ganze Zahl von 1 bis 5 bedeutet, einsetzt.

3. Verfahren nach Anspruch 2, dadurch gekennzeichnet, daß R eine Phenyl-, Naphthyl-, α-Thienyl-, β-Thienyl-, α-Furyl-, β-Furyl, α-Pyridyl-, β-Pyridyl- oder γ-Pyridylgruppe bedeutet, die gegebenenfalls durch X_m oder Y substituiert sein kann, wobei X, Y, m und n die oben genannte Bedeutung haben.

4. Verfahren nach Anspruch 3, worin R eine Gruppe der Formel

bedeutet, worin X, Y, m und n die oben genannte Bedeutung besitzen.

5. Verfahren nach Anspruch 2, worin der Vinyläther mit wenigstens einem halogenierten Ethylen copolymerisiert wurde.

6. Verfahren nach Anspruch 5, worin der Vinyläther mit Tetrafluorethylen copolymerisiert wurde.

7. Verfahren nach Anspruch 6, worin das Copolymer die Strukturformel

besitzt, worin Z für eine ganze Zahl wiederkehrender Einheiten steht.

8. Verfahren nach Anspruch 7, worin das Copolymere ein Äquivalenzgewicht von 1100-1800 besitzt.

9. Verfahren nach Anspruch 1, worin der Katalysator ein Copolymer eines Vinyläthers der Formel

ist worin M für ein Fluoratom, eine Hydroxy- oder Aminogruppe oder eine Gruppe der Formel -OMe steht, worin Me ein Alkalimetall oder eine quarternäre Ammoniumgruppe bedeutet, und Tetrafluorethylen ist.

10. Verfahren nach Anspruch 1, worin der Katalysator ein Copolymer aus einem Vinyläther der Formel

und Tetrafluorethylen ist.

11. Verfahren nach Anspruch 1, worin der Katalysator ein Copolymer aus einem Vinyläther der Formel

worin Me für ein Alkalimetall oder eine quaternäre Ammoniumgruppe steht, und Tetrafluorethylen ist.